What Not to Use

Some antiretroviral (ARV) regimens or components are not generally recommended because of suboptimal antiviral potency, unacceptable toxicities, or pharmacologic concerns. These are summarized below.

Antiretroviral Drugs Not Recommended

The following ARV drugs are no longer recommended for use because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns: delavirdine (DLV), didanosine (ddI), indinavir (IDV), nelfinavir (NFV), and stavudine (d4T).

These regimens are inferior to triple-drug combination regimens (AI).9

Triple-NRTI regimens.

Triple-NRTI regimens have suboptimal virologic activity10-12 or a lack of data (AI).

Antiretroviral Components Not Recommended

Atazanavir (ATV) + indinavir (IDV).

Both of these PIs can cause Grade 3 to 4 hyperbilirubinemia and jaundice. Additive adverse effects may be possible when these agents are used concomitantly. Therefore, these two PIs are not recommended for combined use (AIII).

Cobicistat plus Ritonavir as Pharmacokinetic Enhancers

This combination may be prescribed inadvertently, which may result in additive CYP3A4 enzyme inhibition and may further increase the concentrations of ARV drugs or other concomitant medications (see Tables 18a and 18d).

Didanosine plus Stavudine

The combination of ddI and d4T can result in peripheral neuropathy, pancreatitis, and lactic acidosis, and it has been implicated in the deaths of several pregnant women (AII). 13

Excess clinical adverse events and treatment discontinuation were reported in patients randomized to receive treatment with two non-nucleoside reverse transcriptase inhibitors (NNRTIs).21 Efavirenz (EFV) and nevirapine (NVP) are enzyme inducers, and both of these drugs can reduce concentrations of etravirine (ETR) and rilpivirine (RPV) (AI). 22

Emtricitabine plus Lamivudine

Both drugs have similar resistance profiles and have minimal additive antiviral activity. Inhibition of intracellular phosphorylation may occur in vivo (AIII). 23

Etravirine plus Unboosted Protease Inhibitor

ETR may induce the metabolism and significantly reduce the drug exposure of unboosted PIs. Appropriate doses of the PIs have not been established (AII). 22

Etravirine plus Fosamprenavir/Ritonavir

ETR may alter the concentrations of these PIs. Appropriate doses of the PIs have not been established (AII). 22

The virologic benefit of these PIs has been demonstrated only when they were used with concomitant RTV, or in the case of DRV, also with COBI (AII).

Stavudine plus Zidovudine

These NRTIs are antagonistic in vitro28 and in vivo29 (AII).

Tenofovir Alafenamide plus Tenofovir Disoproxil Fumarate

This combination may be prescribed inadvertently, especially during transition from one formulation to another. There is no data supporting any potential additive efficacy or toxicity if TAF and TDF are used in combination.

• High rate of early virologic nonresponse seen when triple-NRTI combinations, including ABC/TDF/3TC and TDF/ddI/3TC, were used as initial regimen in ART-naive patients. • Other triple-NRTI regimens have not been evaluated.

• ABC/ZDV/3TC (BI) and possibly TDF + ZDV/3TC (BII) in patients in whom other combinations are not desirable

Antiretroviral Components Not Recommended as Part of an Antiretroviral Regimen

ATV + IDV (AIII)

• Potential additive hyperbilirubinemia

• No exception

ddI + d4T (AII)

• High incidence of toxicities: peripheral neuropathy, pancreatitis, and hyperlactatemia • Reports of serious, even fatal, cases of lactic acidosis with hepatic steatosis with or without pancreatitis in pregnant women

• Clinicians caring for patients who are clinically stable on regimens containing TDF + ddI should consider altering the NRTIs to avoid this combination.

2-NNRTI combination (AI)

• When EFV combined with NVP, higher incidence of clinical adverse events seen when compared with either EFV- or NVP-based regimen. • Both EFV and NVP may induce metabolism and may lead to reductions in ETR exposure; thus, they should not be used in combination with ETR.

• No exception

EFV in first trimester of pregnancy or in women with significant childbearing potential (AIII)

• Teratogenic in nonhuman primates

• When no other ARV options are available and potential benefits outweigh the risks (BIII)

FTC + 3TC (AIII)

• Similar resistance profiles • No potential benefit

• No exception

ETR + unboosted PI (AII)

• ETR may induce metabolism of these PIs; appropriate doses not yet established

• No exception

ETR + RTV-boosted ATV or FPV (AII)

• ETR may alter the concentrations of these PIs; appropriate doses not yet established

Brenner BG, Thomas R, Blanco JL, et al. Development of a G118R mutation in HIV-1 integrase following a switch to dolutegravir monotherapy leading to cross-resistance to integrase inhibitors. J Antimicrob Chemother. Jul 2016;71(7):1948-1953. Available at https://www.ncbi.nlm.nih.gov/pubmed/27029845.